Tetrahydropyrimidinyl phenyl carbonyl acid addition salts and related compounds

ABSTRACT

This invention is concerned with tetrahydropyrimidinyl phenyl carbonyl acid addition salts, imidazolinyl phenyl carbonyl acid addition salts, dihydroimidazoisoindolols, tetrahydropyrimidoisoindolols, and tetrahydropyrimidoisoindolol acid addition salts which are all pharmacologically efficacious as anti-depressants. The tetrahydropyrimidinyl phenyl carbonyl acid addition salts, the tetrahydropyrimidoisoindolols and the tetrahydropyrimidoisoindolol acid addition salts are also efficacious as diuretics while the imidazolinyl phenyl carbonyl acid addition salts and the dihydroimidazoisoindolols are efficacious as anorexiants. This invention is also concerned with several processes for the preparation of these compounds.

United States Patent Sulkowski Aug. s, 1975 Inventor: Theodore S.Sulkowski, Wayne. Pa.

American Home Products Corporation. New York. NY.

Filed: Sept. 5. 1973 Appl. No.: 394,616

Related US. Application Data Division of Ser. No. 757.792. Sept. 5.1968. Pat. No. 3.763.178. which is a continuation-in-part of Ser. Nos.622.918. March 14. 1967. abandoned. and Ser. No. 622.931. March 14.1967. abandoned. and Ser. No. 576.833. Sept. 2. 1966, abandoned, andSer. No. 487.587. Sept. 15, 1965. abandoned.

Assignee:

[52] US. Cl... 260/256.4 F; 260/251 A; 260/251 R; 260/256.5 R; 260/256.4H; 260/309.6; 260/326.1 l [51] Int. Cl. C07D 239/06; C07D 487/14 [58]Field of Search..... 260/251 A. 251 R. 256.4 O, 260/256.5 R

[561 References Cited UNlTED STATES PATENTS 3.444.181 5/1969 Houlihan260/3096 3.763.178 10/1973 Sulkowski ..260/309.6

OTHER PUBLICATIONS Metlesics. et al., J. Org. Chem. (33). No. 7, pp2874-2877. (July 1968).

Primary Examiner-Donald G. Daus Assistant E.\'aminerDiana G. RiversAttorney, Agent, or FirmStephen Venetianer [57] ABSTRACT This inventionis concerned with tetrahydropyrimidinyl phenyl carbonyl acid additionsalts, imidazolinyl phenyl carbonyl acid addition salts.dihydroimidazoisoindolols, tetrahydropyrimidoisoindolols. andtetrahydropyrimidoisoindolol acid addition salts which are allpharmacologically efficacious as antidepressants. Thetetrahydropyrimidinyl phenyl carbonyl acid addition salts, thetetrahydropyrimidoisoindolols and the tetrahydropyrimidoisoindolol acidaddition salts are also efficacious as diuretics while the imidazolinylphenyl carbonyl acid addition salts and the dihydroimidazoisoindololsare efficacious as anorexiants. This invention is also concerned withseveral processes for the preparation of these compounds.

14 Claims, N0 Drawings TETRAI-IYDROPYRIMIDINYL PIIENYL CARBONYL ACIDADDITION SALTS AND RELATED COMPOUNDS This is a division. of applicationSer. No. 757,792, filed Sept. 5, 1968, now US. Pat. No. 3,763.l 78,which application is a continuation-in-part of US. Pat. applications,Ser. No. 622,918, entitled Tctrahydropyrimidinyl Phenyl Carbonyl andlmidazolinyl Phenyl Carbonyl Compounds", filed Mar. l4, 1967; Ser. No.622,93 l, entitled Process For the Preparation of lmidazolinyl PhenylCarbonyl Compounds", filed Mar. 14, 1967; Ser. No. 576.833, entitled2-(3- Aminopropyl) lsoindoles and Related Compounds", filed Sept. 2,1966; and Ser. No. 487,587. entitled 1,2- ,3,4,6,l 0b-Hexahydropyrimido[2, l -a]lsoindol-6-Ones and Related Compounds," filed Sept. 15, l965 andall now abandoned.

This invention relates to bicyclic and tricyclic nitro gen containingcompounds as well as to novel methods for their preparation. Inparticular, the present invention is concerned withtetrahydropyrimidinyl phenyl carbonyl acid addition salts.tetrahydropyrimidoisoindolols and tetrahydropyrimidoisoindolol acidaddition salts which in standard and accepted pharmacological tests havedemonstrated both antidepressant and diuretic activities. Further, it isconcerned with imidazolinyl phenyl carbonyl acid addition salts anddihvdroimidazoisoindolols which in standard and accepted pharmacologicaltests have demonstrated both antidepressant and anorexiant activities.

The new and novel compounds which are included within the scope of thisinvention are represented by the following formulae;

wherein R, and R are selected from the group consisting of hydrogen,lower alkyl, phen(lower)alkyl, phenyl, monochalophenyl, dihalophenyl,mono(lower)alkylphenyl, di-(lower)alkylphenyl, trifluoromethylphenyl,mono(lower)alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, furyland tetrahydro-2- naphthyl, with the provision that R is hydrogen, loweralkyl and phen(lower)alkyl when n is 2; R is selected from the groupconsisting of hydrogen, halogen, amino, lower alkylamino, lower alkyland lower alkoxy; R is hydrogen when R andR are dissimilar and when Rand R are the same they are both selected from the group consisting ofhydrogen, halogen, lower alkyl and lower alkoxy; R is selected from thegroup consisting of phenyl, monohalophenyl, dihalophenyl,mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl,mono(lower)alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, furyland tetrahydro-Z-naphthyl; n is an integer from 1 to 2; and HX is apharmacologically acceptable acid addition salt. As employed herein theterms lower alkyl, lower alkoxy and the like are meant to include bothbranched and straight chain moieties containing from one to about sixcarbon atoms.

The new and novel compounds of this invention which are represented bystructural formula (I) wherein n is l are called Imidazolinyl PhenylCarbonyl Acid Addition Salts. Typical examples thereof are:2(2-imidazolin-2-yl) benzophenone hydrochloride and4-chloro-2-(2-imida2olin-2-yl)benzophenone hydrochloride. Alternatively,those compounds of structural formula (I) wherein n is 2 are named:tetrahydropyrimidinyl Phenyl Carbonyl Acid Addition Salts, such as, 2-(3 ,4,5 ,6-tetrahydro-2-pyrimidinyl )-4- methylbutyrophenonehydrochloride and 2-phenyl-2- (3 ,4,5 ,6-tetrahydro-2-pyrimidinyl)acetophenone hydrochloride.

The new and novel compounds of this invention N (OH2) R /i 2 H andwherein R R and R are defined as above. Various oxidation processes willreadily suggest themselves to those skilled in the art. For example, theparticular 2-(3-aminopropyl)isoindol (A) may be dissolved in areaction-inert solvent, e.g. an alkanol. and purged with oxygen or airuntil the oxidation is complete. Alternatively. the oxidation may beaccomplished by contacting the 2-(3-aminopropyl) isoindole solution withan s oxidizing agent, such as potassiumdichromate, potassium chlorate.or potassim permanganate. The oxidation reaction may be conducted in anysuitable reaction-inert solvent. Many such solvents will readily suggestthemselves to one skilled-in the art of organic chemistry.

When the aforesaid oxidation is complete, the product is separated bystandard recovery methods, such as, concentration, filtration andcrystallization. The tetrahydropyrimidoisoindolols (B) may then berecrystallized from an appropriate solvent, such as dimethylformamideand dimethylacetamide.

In accord with the new and novel second process of the presentinvention, the dihydroimidazoisoindolols of this invention may besynthesized by the following schematic sequence of reactions:

i C R2 N R2 CH2 CH2 NH2 NH CH HX 3 R3 I N R2 5' R2 H R -1/2 H2 50 R3 2%R3 OH 5 wherein R R and R are defined as above, R,; is aryl and alkyl,for example: lower alkyl, phenyl,

monohalophenyl, dihalophenyl, mono(lower)alkylphenyl,di(lower)alkylphenyl and alkoxyphenyl, and X is the anion portion ofamineral acid. The rearrangement of a tetrahydroimidazoisoindolone offormula l is effected by contacting the particular compound l with amineral acid. This reaction may be accelerated by heating and stirringthe reaction mixture until the pre- *l N R 1 R 9 [I] H R 7 eipitation ofthe 2-( aminoethyl )-3- hydroxyphthalimidine mineral acid addition salt,as designated in formula (2), is complete. The phthalimidine (2) isseparated by filtration or decantation and either recrystallized from asuitable solvent, such as water, a lower alkanol and dioxan, or admixeddirectly with a substantially equimolar quantity of an aryl or alkylsulfonyl halide in pyridine. The reaction mixture is then heated to atemperature from about 80C. to about 115C. for a period from about twohours to about ten hours. Preferably, this reaction is conducted at thereflux temperature of the reaction mixture for a period of about 2hours. After the above reaction is complete. the product ofsulfonyltetrahydroimidazoisoindolone (3) is recovered by customaryisolation procedures.

The above prepared sulfonyltetrahydroimidazoisoindolone (3) maybehydrolyzed and rearranged by admixture with from about 80 to about 100percent sulfuric acid. The product of this hydrolysis, the sulfate saltof an imidazolinyl phenyl carbonyl compound, as shown in formula (4)which may be recovered as such by conventional means. Alternatively, thereaction mixture is neutralized by the addition of a base and theresulting precipitate recrystallised from an appropriate organic solventsuch as lower alkanol, dioxan, dimethylformamide and dimethylacetamideto afford an appropriate dihydroimidazoisoindolol (5).

As a new and novel alternative to the second process of the presentinvention, it has been found that the dihydroimidazoisoindolols of thisinvention may also be prepared by directly reacting atetrahydroimidazoisoindolone l with an aryl or alkyl sulfonyl halideunder the above-described reaction conditions to afford an appropriatesulfonyltetrahydroimidazoisoindolonc 3 Thereafter, this compound (3) isfurther reacted hereinbefore described to yield an imidazolinyl phenylcarbonyl sulfate salt (4) which may then be neutralized to afford adihydroimidazoisoindolol (5).

As a further alternative to the second process of the present invention.it should be noted that the 2- (aminoethyl)-3-hydroxyphthalimidine (2)intermediates can also be prepared by the condensation of an acidchloride of an o-carbonyl benzoic acid with ethylene diamine describedby Sulkowski et al in J. Org. Chem. 32, 2180 (1967).

In accord with the new'and novel third process of the present invention,some of the dihydroimidazoisoindolols of this invention may be preparedby the procedure which is exemplified by the following reaction scheme:

wherein R is selected from the group consisting of lower alkyl, phenyl,lower alkylphenyl, lower alkoxyphenyl, di(lower)alkylphenyl,di(lower)alkoxyphenyl, aminophenyl, trifluoromethylphenyl,monohalophenyl, dihalophenyl, fury], thienyl and naphthyl; R is selectedfrom the group consisting of hydrogen, halogen, lower alkyl and loweralkoxy; R is hydrogen when R,, and R are dissimilar and when R and R arethe same they are both selected from the group consisting of hydrogen,halogen, lower alkyl and lower alkoxy.

The oxidation reaction is effected by contacting an appropriatehexahydrobenzodiazocine (a) with an oxidizing agent in a reaction-inertsolvent at a temperature from about 20C. to about 60C. for a period ofabout /2 to about 4 hours. Preferably, this reaction is conducted bycontacting an aqueous solution of a hexahydrobenzodiazocine salt with apotassium permanganate solution at room temperature for about one hour.Many other oxidizing agents and reaction-inert solvents which may beemployed in this reaction will readily suggest themselves to thoseskilled in the art. In this regard, excellent results can be obtainedwhen potassium dichromate and potassium chlorate are employed as theoxidizing agents. By reaction-inert solvent as employed herein is meanta solvent which will dissolve the hexahydrobenzodiazocine and notinterfere with the ,oxidation reaction, such as, water while acetone andmethyl ethyl ketone may be employed as solvents when potassiumpermanganate is employed as the oxidizing agent.

When the oxidation reaction is complete, the correspondingdihydroimidazoisoindolol (b) may be separated and recovered by routinemeans, for example, precipitating the product by the addition of a baseand then separating it by decantation or filtration. The time andtemperature ranges employed in the aforesaid reactions are not criticalbut simply represent the most convenient range consistent with carryingout these reactions in a minimum of time without undue difficulty. Thusreaction temperatures appreciably below these can be used, but their useconsiderably extends the reaction time. Similarly, reaction temperatureshigher than those mentioned can be employed with a concomitant decreasein reaction time. The 2-(3- aminopropyl)isoindoles (A) employed asstarting materials in the first above described process for thepreparation of the tetrahydropyrimidoisoindolol compounds (B) of thisinvention are known compounds which are described in co-pending UnitedStates Pat. application, Ser. No. 622,917, entitled lsoindoles,lsoindolines and Related Compounds, filed on Mar. 14, 1967, by theodoreS. Sulkowski which is a continuation-in-part of U.S. Pat. applications,Ser. No. 576,833, entitled 2-(3-Aminopropyl)lsoindoles and RelatedCompounds, filed Sept. 2, 1966 and Ser. No.

487,587, entitled 1 ,2,3,4,6, 1Ob-l-lexahydropyrimido[2,1-a]Isoindol-6-Ones, filed Sept. 15, 1965 andnow abandoned. The tetrahydroimidazoisoindolones (1) and thehexahydrobenzoidazocines (a) which are respectively employed as startingmaterials in the second and third above described process for thepreparation of the dihydroimidazoisoindolols (5) of this invention areknown compounds which are described in co-pending U.S. Pat. application,Ser. No. 609,779, entitled Benzodiazoeines, filed on Jan. 17, 1967, byTheodore S. Sulkowski, which is a continuation-in-part of U.S. Pat.applications, Ser. No. 554,672, entitled Benzodiazocines, filed on June2, 1966; Ser. No. 444,050, entitled Substituted 3,4-Dihydro-6-Aryl-2,5-Benzodiazocin-l (2H)-Ones and Related Compounds, filed on Mar. 30, 1965and now abandoned; and Ser. No. 272,216, entitled Substituted3,4-Dihydro-6- Aryl-2,5-Benzodiazocin-1(2H)-Ones and Related Compounds,filed on Apr. 11, 1963 and now abandoned. The aryl or alkyl sulfonylchlorides used in this latter process are well known chemicals which arecommercially available or may easily be prepared by well known chemicalprocedures.

The tetrahydropyrimidoisoindolols (B) of the present invention were atfirst thought to be Hexahydropyrimidoisoindolones and were so describedin the first prior filed parent application (U.S. Ser. No. 487,587).Subsequently, these compounds were reexamined and then thought to beTetrahydropyrimidinyl Phenyl Carbonyl Compounds" and were so defined inthe following two subsequently filed parent applications U.S. Ser. Nos.576,833 and 622,918). It has now been concluded, based on the nature ofthe starting materials; the mode of synthesis; the elemental analysis;and the ultra violet and infra red spectrographic analyses, that all thesolid bases prepared by the first process of this invention areTetrahydropyrimidoisoindolols (B). Further, since these nitrogencontaining tetrahydropyrimidoisoindolols are basic in nature they willreact with pharmacologically acceptable acids to form acid additionsalts. Such acids are well known in the art, for example, hydrochloric,hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, acetic, lactic,citric, tartaric, maleic, gluconic, benzenesulfonic, toluenesulfonic,methylsulfonic, ethylsulfonic acids and the like. These salts may beprepared by procedures commonly employed in the art, for example,reacting the compound with an equivalent of the selected acid in aqueoussolution and concentration of the solution. Other known procedures mayalso be employed, e.g., the procedure of Example VIII.

The ultra violet spectrographic analyses of thetetrahydropyrimidoisoindolols (B) of this invention and their acidaddition salts which are substituted in the 6- position with an aromaticgroup, e.g. phenyl, monohalophenyl, dihalophenyl,mono(lower)alkylphenyl, di(lower,)alkylphenyl, trifluoromethylphenyl,mono(lower)alkoxyphenyl, di(lower) alkoxyphenyl, thienyl, pyridyl,furyland tetrahydro-2-naphthyl, demonstrate an absence of absorption inthe 250 a region indicating that both the bases and salts possess thesetetrahydropyrimidoisoindol structures in solution. Alternatively, ultraviolet analyses of neutral and acidic solutions of thesetetrahydropyrimidoisoindolols (B) and their acid addition salts whichare unsubstituted, e.g. hydrogen or substituted in the 6-position withan aliphatic or aralkyl group, e.g. lower alkyl and phen(- lower)alkyldemonstrate absorption in the 235-240 ,a region indicating that theirstructures in solution are predominately the tetrahydropyrimidinylphenyl carbonyl compounds of the structure:

wherein R and R are defined as above and R is hydrogen, lower alkyl andphen(lower)alkyl. Further, the infra red spectrographic analyses ofthese latter compounds determined by the procedure of Hofmann et al,Analyt. Chem., Vol. 39, pg. 406 (1967) also indicates that the solidacid addition salts thereof also exist in the above showntetrahydropyrimidinyl phenyl carbonyl forms.

The dihydroimidazoisoindolols (5) of the present invention were firstthought to be Tetrahydroimidazoindolones and were so described in thefirst prior filed parent application. Subsequently, these compounds werere-examined and then thought to be lmidazolinyl Phenyl CarbonylCompounds and were so defined in the following three subsequently filedparent applications (U.S. Ser. Nos. 576,833, 622,931 and 622,918). Ithas now been concluded, based on the nature of the starting materials;mode of synthesis; the elemental analysis; and ultra violet and infrared analyses, that all the solid bases prepared by the second and thirdprocess of this invention are -Dihydroimidazoisoindolols (5 Further,since these nitrogen containing dihydroimidazoisoindolols are basic innature they also will react with pharmacologically acceptable acids asdescribed vabove to form acid addition salts.

The ultra violet spectrographic analyses of the dihydroimidazoisoindolols (5) of this invention in neutral solutiondemonstrate an absence of absorption in the 250 p. region indicatingthat these bases also possess these dihydroimidazoisoindolol structureswhen they are dissolved in a non-acidic solution. Alternatively, theultra violet analyses of acid solution of these bases and the neutralsolutions'of their acid addition salts demonstrate absorption in 250 aregion indicating that they are imidazolinyl phenyl carbonyl. compoundsin solution of the structure: I

where R R and R are defined as above. The infra red spectrographicanalyses of these compounds also indicates that the solid bases aredihydroimidazoisoindolols .while their corresponding solid acid additionsalts exist in the above shown imidazolinyl phenyl carbonyl forms.

The tetrahydropyrimidinyl phenyl carbonyl acid addition salts (formula Iwhere n is 2); the tetrahydropyrimidoisoindolols (formula ll where n is2); and the tetrahydropyrimidoisoindolol acid addition salts (formulalll) of the present invention have been found to possess valuablepharmacological activity. More particularly, these compounds haveexhibited utility, in standard pharmacological tests, as anti-pressantand diuretic agents.

In the pharmacological evaluation of the antidepressant property ofthese compounds (1, n=2; ll, 11 2; and lll), the in vivo anti-depressantactivity is evaluated by the procedure described by Rubin et al, inJ.P.E.T. 120, 125 l957). When tested by this procedure, these compoundsdemonstrate useful antidepressant activity, e.g. having mood elevatingproperties as psychic energizers, when they are administered orally tomice in a dosage range from about I to about 100 mg./kilo of animal bodyweight. Further, the in vivo diuretic activity of these compounds (I, 112; ll, 11 2; and III) is evaluated by the procedure described byLipschitz et al, in J. Pharmacol. 79, 97 (1943). When tested by thisprocedure these compounds demonstrate useful diuretic activity when theyare administered orally to rats in a dosage range from about 0.25 toabout 25 mg./kilo of animal body weight.

The imidazolinyl phenyl carbonyl acid addition salts (formula I where nis l) and the dihydroimidazoisoindolols (formula ll where n is l) of thepresent invention have also been found to possess valuablepharmacological activity. In particular, these compounds have exhibitedutility, in standard pharmacological tests, as antidepressant andanorexiant agents.

In the pharmacological evaluation of the antidepressant property ofthese compounds (I, n=l and II, n =1 the in vivo anti-depressantactivity is also evaluated by the procedure described by Rubin et a], inJ.P.E.T. 120, 125 (1957). When tested by this procedure, these compoundsdemonstrate useful anti depressant activity, e.g. having mood elevatingproperties as psychic energizers, when they are administered orally tomice in a dosage range from about 1 to about mgjkilo of animal bodyweight. Further, the in vivo anorexiant activity of these compounds (I,n=l and Il, n=l e.g. appetite suppressant effects is evaluated by thefollowing procedure:

Male Charles River rats between 120 and 140 grams are trained to drinksweetened condensed milk from a graduated drinking tube. After a shortlearning period the animals are placed on a routine of water ad lib for24 hours, standard laboratory chow for 22 hours and sweetened condensedmilk for 2 hours. The volume of milk consumed is measured at /2 hour aswell as 2 hours and the aniamls are weighed daily. This schedule ismaintained 5 days a week over a period of several months. Trials are runon the same day each week and changes in milk consumed and 24 hourweight changes are compared to the average of the 2 days before the testcompound is administered. Animals are tested as groups of six and onegroup is given saline each week to serve as controls. The test compoundsare usually administered intraperitoneally in saline and/or orally inwater.

The imidazolinyl phenyl carbonyl acid addition salts and thedihydroimidazoisoindolols of this invention in the above test procedurewhen administered orally to rats at a dose of IO mg./kg. induce adecrease in food consumption of about 40 percent in the first half hourand about 20 percent in 2 hours with a concurrent total average weightloss of about /2 a gram/animal in 24 hours. When administeredintraperitoneally at a dose of lO mg./kg., these compounds (I, n=l andII, n=l) induce a decrease in food consumption of about percent in thefirst half hour and about 65 percent in 2 hours with a concurrent total24 hour average weight loss of about 7 /2 grams/animal.

When the tetrahydropyrimidinyl phenyl carbonyl acid addition salts; thetetrahydropyrimidoisoindolols and the tetrahydropyrimidoisoindolol acidaddition salts of this invention are employed as antidepressant anddiuretic agents and when the imidazolinyl phenyl carbonyl acid additionsalts and the dihydroimidazoisoindolols of this invention are employedas anti-depressant and anorexiant agents, they may be administered tomammals, e.g. mice, rats, rabbits, dogs, cats, monkeys, etc. alone or incombination with pharrnacologically acceptable carriers, the proportionof which is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard biologicalpractice. For example, they may be'adrninistered orally in the solidform containing such excipients as starch, milk sugar, certain types ofclay and so forth. They may also be administered orally in the form ofsolutions or they may be injected parenterally. For parenteraladministration they may be used in the form of a sterile solutioncontaining other solutes, for example, enough saline or glucose to mathe solution isotonic.

The dosage of the compounds of this invent. in will vary with the formof administration and the p irticular compound chosen. Furthermore, itwill vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimumdose of the compound. Thereafter. the dosage is increased by smallincrements until the optimum effect under the circumstances is reached.In general, the compounds of this invention are most desirablyadministered at a concentration level that will generally affordeffective results without causing any harmful or deleterious sideeffects.

The following examples are given by way of illustration and are not tobe construed as limitations of this invention, many variations of whichare possible without departing from the scope and spirit thereof.

EXAMPLE I The 2'(3-aminopropyl)-l-(4- chlorophenyl)isoindole,hydrochloride (Zgms) is dissolved in water and neutralized with a sodiumcarbonate solution. The regenerated base is extracted with ethylacetate, dried over magnesium sulfate and evaporated to dryness. Theresidue is dissolved in 250 ml. of ethanol and air is bubbled throughthe solution for 48 hours. The precipitated white crystalline solid isseparated by filtration and upon recrystallization fromdimethylformamide the re is obtained 6-( 4- chlorophenyl )-2,3,4,6-tetrahydropyrimido[ 2, 1- a]isoindol-6-ol, m.p. 2746C. dec., whichis insoluble in water and soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 224 mp. (F23,000),infl. 243 mp. (F12,000), max. 267 mp. (F3,800); Ultra Violet Absorption(pH l) max. 223 mp (F2l,l00), infl. 243 mp. (F14,200), max. 267 mp(F3,800); Infra Red Absorption (KBr) c l24ll0300ll l Cald for C H ClN O:C, 68.33; H, 5.06; N, 9.33; C1, 11.87.

Found: C, 68.12; H, 5.39; N, 9.22; Cl, 11.85.

The above prepared tetrahydropyrimidoisoindolol is dissolved in ethanoland admixed with an aqueous solution containing an equivalent amount ofhydrochloric acid. The mixture is stirred for ten minutes and thesolvent removed by evaporation. ln this manner, is obtained6-(4-chlorophenyl)-2,3,4,6- tetrahydropyrimido[2, l -a]isoindol-6-olhydrochloride, m.p. 2324C., as a white crystalline solid, which issoluble in hot water.

Analysis: Ultra Violet Absorption (95% ETOH) max. 224 mp. (F23,000),infl. 243 mp (F14,000), infl. 268 mp (F3,8O); lnfra Red Absorption (KBr)1675 cm, 2600-3300 cm.

Calcd for C,-,H,,=,ClN O.HCl: C, 60.91; H, 4.81; N, 8.36; Cl, 21.16.

Found: C, 60.91; H, 5.06; N, 8.31; Cl, 21.1.

EXAMPLE 11 The procedure of Example 1 is repeated reacting anappropriate 2-(3-aminopropyl)isoindole with an oxidizing agent, e.g.potassium dichromate, potassium chlorate and hydrogen peroxide to affordthe hereinafter listed products:

2-(3-AM1NOPROPYL)1SO1NDOLES PRODUCTS 8-bromo-2.3,4,6-tetrahydro-6-(4-tolyl)pyrimidol 2,1-a] isoindol-(m-ol 2,3 ,4,6-tetrahydro-9-methyl-fi-propylpyrimido 12,1-a lisoindol-6-ol 2,3,4,6-tetrahydrol0- 2-(3-aminopropy1)-6-br l. -tolyl )isoindole 2-(3-aminopropyl)-5-methyl-1-propylisoindole 2-( 3-aminopropyl )-4-iodoistr indole iodopyrimidoI 2. l-a ]isoindol 8,9-dibromo 6-( 4-brom0- phenyl 2.3 ,4,6tetrahydropyrimidol2.1-alisoindol- 2-( B-aminopropyl l 4-bromopherlyl )-5,6-dihromoisoindole -o 2.3.4.6-tetrahydro-6-( 2,4- dimethoxyphenyl)pyrimido I 2, l -a lisoindol-6-ol 2-( 3-aminopropyl l 2.4-dimethoxyphenyl )isoindole EXAMPLE lll further purification, the 2-(3-aminopropyl)-lphenylisoindole is dissolved in 200 ml. of ethanol andoxygen is bubbled through the solution for 48 hours. The precipitatedsolid is separated by filtration and on recrystallization fromdimethylformamide there is obtained2,3,4,6-tetrahydro-6-pheny1pyrimido[2,1- a]isoindol-6-ol, m.p. 2557C.dec., as white prisms which is insoluble in water and slightly solublein hot dimethylacetamide.

Analysis: Ultra Violet Absorption ETOH) max. 233 mp (Fl4,000), max. 268mp (F4,000), infl. 271 mp (F3,000); Ultra Violet Absorption (pHl) max.239 mp. (Fl4,900), infl. 271 mp (F3,000); Infra Red Absorption (KBr)1650 cm, 2300-3000 cm".

Calcd for C H N O: C, 77.25; H, 6.10; N, 10.60.

Found: C, 77.36; H, 6.05; N, 10.51.

The above reaction is repeated in anhydrous diisopropyl ether at 60C.for 2 hours with similar results.

In a similar manner, starting with 10b-(3,4'- dichlorophenyl l ,2,3,4,6,l Ob-hexahydropyrimido[2,l-alisoindol-6-one there is obtained 6-(3,4-dichlorophenyl )-2,3,4,6-tetrahydropyrimido 2, 1 a]isoindol-6-ol,m.p. 2679C., as a white crystalline solid which is insoluble in waterand slightly soluble in hot dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) infl. 230 mp (F22,600),max. 268 mp. (F4,500); infl. 282 mp. (F2,000); Ultra Violet Absorption(pHl) max. 228 mp. (F22,000), max. 268 mp. (F4,700); infl. 282 mp (F1,600); Infra Red Absorption (KBr) 1650 cm", 2300-3000 cm".

Calcd for C H CI N O: C, 61.27; H, 4.24; N, 8.41; CI, 21.29.

Found: C, 61.41; H, 4.28; N, 8.46; CI, 21.2.

EXAMPLE 1V 2 3-Aminopropyl l-( 4-bromophenyl )isoindole (4.0 gms.) isdissolved in ml. of ethanol and oxidized by bubbling oxygen through thesolution for 36 hours. The precipitated solid is separated bydecantation and recrystallized from dimethylformamidc. In this manner,is obtained 6-(4-bromophenyl)-2,3,4,6- tetrahydropyrimido[ 2, l-a]isoindol-6-ol, m.p. 2789C. dec., as a white crystalline solid whichis insoluble in water and slightly soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 228 mp (F22,500), max.267 mp (F4300); Ultra Violet Absorption (pHl max. 229 mp (F21,500), max.267 mp (F4,3O0); lnfra Red Absorption (KBr) 1645 cm", 2300-2900 cm"'.

Cald for C H BrN O: C, 59.48; H. 4.41; N, 8.16.

Found: C, 59.51; H, 4.36; N, 8.26.

Similarly. utilizing anhydrous ethylene glycol dimethyl ether as thesolvent, 6-(2,4-dibromophenyl)- 2,3,4,6-tetrahydropyrimido[ 2, l-a]isoindo1-6-ol is synthesized.

EXAMPLE V 2-( 3-Aminopropyl l 5 ',6',7 ',8 '-tetrahydro-2naphthyl)isoindole (3.0 gms.) is dissolved in 250 ml. of benzene andoxidized by bubbling oxygen through the solution for 60 hours. Theprecipitate is separated by filtration and recrystallized fromdimethylacetamide. In this manner, is obtained 6-(5,6,7,8-tetrahydro-2-naphthyl)-2.3,4,6-tetrahydropyrimidol2, 1 -a]isoindol- 6-ol, m.p.253-5C. dec., as a white crystalline solid which is insoluble in waterand soluble in hot dimethyl acetamide.

Analysis: Ultra Violet Absorption (95% ETOH) 230 mu (6 10.000). infl.245 1T1,LL (F9,200), max. ma (F3,200); Ultra Violet Absorption (pHlinfl. 230 mp. (F10,900), infl. 245 my (Fl0,()), max. 270 m (F3,200);Infra Red Absorption (KBr) 1655 cm, 2300-3000 cm".

Calcd for C- H- N O: C, 79.21; H, 6.96; N, 8.80.

Found: C. 78.96; H. 7.15; N, 8.95.

In a similar manner, 6-(4-trifluoromethylphenyl)- 2,3,4,6-tetrahydropyrimido[ 2, l -a]isoindol-6-ol; 6-( 2-trifluoromethylphenyl )-2,3,4,6-

tetrahydropyrimidol'l. l -a]isoindol-6-ol: and 6-furyl- 2,3,4.6-tetrahydropyrimidol 2, 1 -a]isoindol-6-ol are produced.

EXAMPLE Vl Repeating the procedure of Example'V but starting with 2-(3-aminopropyl)- 1 -methylisoindole, there is obtained 2,3,4.6-tetrahydro-6-methylpyrimido[ 2, l a]isoindol-6-ol, m.p. l99-210C.,as a white crystalline solid which is insoluble in water and soluble incli methylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max.

236 mp. (F12.60O), infl. 265 m .t (F4,l00); Ultra Violet Absorption(pH 1) max. 239.5 mp (F14.200), infl. 265 m,u (F4100); Infra RedAbsorption (KBr), 1640 cm", 23003000 cm"; lnfra Red Absorption of the insitu hydrochloride salt by the procedure of Hofmann et a1, Analyt. Chem.Vol. 39, pg. 406 (1967) (KBr) 1670 cm, 1647 cm, 2600-3100 cm".

Calcd for C H N Oz C. 71.26; H, 6.98; N, 13.87.

Found: C, 71.30; H, 6.90; N, 13.63.

In a similar manner. the following compounds are prepared:

2.3.4.6-Tetrahydropyrimidol 2, l-a]isoindol-6-o1, m.p. 2()57C., as awhite crystalline sold which is insoluble in water and slightly solublein dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 235 mp. (Fl2.400),infl. 266.5 mp. (F3,650); Ultra Violet Absorption (pHl) max. 240 my.(F10,800), infl. 266.5 mg. (F3,650); Infra Red Absorption (KBr) 1640 cm,23003000 cm; Infra Red Absorption of 45 the in situ hydrochloride by theabove-identified procedure (KBr) 1670 cm, 2600-3100 cm.

2-(3-AM1NOPROPYL) PHENYLlSOlNDOLES Calcd for C H N O: C, 70.18; H, 6.42;N, 14.88. Found: C, 69.92; H, 6.47; N, 14.71.6-Benzyl-2,3,4,6-tctrahydropyrimido[ 2, l-alisoindol- '6-01. m.p. 2335C.dec., as a white cyrstalline solid which is insoluble in water.

Analysis: Ultra Violet Absorption ETOH) max. 235 mp. (Fl 1,700), infl.269 m,u (F3,900); Ultra Violet Absorption (pH 1) max. 240 mp. (F12,9O0),infl. 269 mp (=3,90()); lnfra Red Absorption (KBr) 1645 cm, 2300-3000cm; Infra Red Absorption of the in situ hydrochloride by theabove-identified procedure (KBr) 1665 cm, 2600-3100 cm.

Calcd for C H N o: C, 77.66; H, 6.52; N, 10.07.

Found: C, 77.67; H, 6.41; N, 9.77.

6-Butyl-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol- 6-01, m.p. 1813C., asa white crystalline solid which is insoluble in water and soluble inethanol and dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 234.5 my. (F12,100),infl. 266 mp. (F4,000); Ultra Violet Absorption (pH 1) max. 240m,u.(Fl4,000), infl. 266 mp. (F4,O0O); Infra Red Absorption (KBr) 1640 cm,2300-3000 cm; Infra Red Absorption of the in situ hydrochloride by theabove-identified procedure (KBr) 1670 cm, 1640 cm", 2600-3100 cm.

Calcd for C H N O: C, 73.73; H, 8.25; N, 11.47.

Found: C, 74.03; H, 7.99; N, 11.63.

6-(3-Amino-4-chlorophenyl)-2,3,4,6- tetrahydropyrimido[2, l-a]isoindol-6-ol, m.p. 2278C. dec., as a white crystalline solid whichis insoluble in water and soluble in hot dimethylacetamide.

Analysis: Calcd for C H C1N O: C, 65.05; H, 5.14; N, 13.39.

Found: C, 65.09; H, 5.49; N, 13.61.

2,3,4,6-Tetrahydro-6-(4-tolyl)-pyrimido[2,1- a]isoindol-6-ol, m.p.2379C., dec., as a white crystalline solid which is insoluble in waterand soluble in dimethylacetamide.

Analysis: Calcd for C H N O:C, 77.67; H. 6.52; N, 10.07.

Found: C, 77.62; H, 6.48; N, 9.94.

EXAMPLE V11 When the procedure of the aforementioned Examples isemployed, the hereinafter listed 2-(3- aminopropyl)phenylisoindoles areoxidized to afford the following products:

TETRAHYDROPYRIMIDO lSOlNDOLOLS 2-( 3-aminopropyl )6-chlorolphenylisoindole 2-( 3-aminopropyl-5-methy1- l-phenylisoindole 2-(3-aminopropyl )-6-ethyluminol -phenylisoindolc 2-( 3-aminopropyl)-5,6-dichlorol-phenylisoindolc 2-( 3 umin0prop l-phenylisoindo 2-(3-aminopropyl l 3,4- 'diiodophenyl )isoindolc 2-(3-aminopropyl l-isopropyl -5.6-dipropoxyisoindole 2(3 uminopropyl)-1-(3,4- diethoxyphenyl )isoindole 'l-5.6-dimethoxy- 6-( Z-trifluoromethylphenyl)-2,3,4,6-

tetrahydropyrimido[2,1-a[isoindol-6-o1 hydrochloride;

6-furyl-2.3,4,6-tctrahydropyrimido[2,1-a]isoindol-6- o1 hydrochloride;

2-( 3 ,4,5 ,6-tetrahydro-2-pyrimidiny1 )acetophenone hydrochloride;

2-( 3,4,5 ,6-tetrahydro-2-pyrimidiny1 )benzaldehyde hydrochloride;

2'-phenyl-2-(3,4,5,6-tetrahydro-2-pyrimidinyl) acetophenonehydrochloride;

2-(3,4,5,6-tetrahydro-2-pyrimidiny1)valerophenone hydrochloride 6-(3-amino-4-chlorophenyl )-2.3,4.6-

tetrahydropyrimido[2,1-a]isoindo1-6-ol hydrochloride;

2,3 ,4,6-tetrahydro-6-( 4-toly1 )pyrimido[ 2, 1

alisoindol-6-ol hydrochloride;

8-chloro-2.3 ,4,6-tetrahydro-6-pheny1pyrimido[ 2, 1

aIisoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-9-methyl-6-phenylpyrimido[2,l-

a]isoindol-6-ol hydrochloride;

8-ethy1amino-2,3,4,6-tetrahydro--phenylpyrimido [2,1-a1isoindo1-6-oldihydrochloride;

8,9-dichloro-2,3,4,o-tetrahydro-6-phenylpyrimido [2,1 -a]isoindo1-6-olhydrochloride;

2,3,4,6-tetrahydro-8,9-dimethoxy--phenylpyrimido [2,1-a]isoindol-6-olhydrochloride;

2,3 ,4,6-tetrahydro-6( 3 ,4-diiodophenyl )pyrimido [2,1-a1isoindol-6-olhydrochloride;

2-(2,3,4,5,6-tetrahydro-2-pyrimidiny1)-2-methyl-4,5-dipropoxypropiphenone hydrochloride;

6-( 3,4-diethoxyphenyl )-2,3,4,6-tetrahydropyrimido [2,1-a]isoindol-6-olhydrochloride;

6-(4-hexylphenyl)-2,3,4,6-tetrahydropyrimido[2,1-

a]isoindol-6-ol hydrochloride; 1

4-amino-2-( 3,4,5 ,6-tetrahydro-2- pyrimidinyl)benzaldehydedihydrochloride;

9-chloro-6-(4-ethylphenyl)-2,3,4,6-

tetrahydropyrimido[2,1-a]isoindol6-ol hydrochloride;

2,3 ,4,6tetrahydro-6-( 2-thieny1 )pyrimido[ 2, 1

alisoindo1-6-ol hydrochloride;

2,3,4.6-tetrahydro-9-mcthyl-6-phenylpyrimido[2,1-

a]isoindo1-6-ol hydrochloride;

2,3 ,4,-tetrahydro--phenyl-7-propylpyrimido[ 2, l

a]isoindol-6-ol hydrochloride;

6-(4-fluoropheny1 )-2,3,4,6-tetrahydropyrimido[2,1

a]isoindol-6-ol hydrochloride;

6-( 3-bromo-4-methylphenyl )-2,3,4,6-

tetrahydropyrimido [2, l -a]isoindol-6-ol chloride;

2,3,4,6-tetrahydro-6-(3-iodophcnyl)pyrimido[2,1-

a]isoindo1-6-ol hydrochloride;

9-amy1-2,3,4,6-tetrahydro- 6-phenylpyrimido a lisoindo1-6-o1hydrochloride;

2.3.4,6-tetrahydro-6-phenyl-8-propylaminopyrimido [2,1a[isoindol-6-oldihydrochloride;

9-butoxy-2,3,4,6-tetrahydro- 6-phenylpyrimido 2,1

alisoindol-6-ol hydrochloride; 7

2,3 .4,6-tetrahydro-6-( 3 ,4-dimethylphenyl )pyrimido [2,1a]isoindo1-6-ol hydrochloride;

2,3,4,6-tetrahydro-6-( 4-propoxyphenyl pyrimido[ 2, 1 -a]isoindol-6-olhydrochloride;

2-( 3,4,5 ,fi-tetrahydro-2-pyrimidinyl )-4.5-dimethy1- benzaldehydehydrochloride;

hydro- 2,3 ,4,o-tetrahydro-6-pyridylpyrimido[ 2, l -a]isoindo1- 6-o1hydrochloride; and

2-( 3 .4,5,o-tetrahydro-2-pyrimidiny1 )-4- methoxyvalerophenonehydrochloride.

EXAMPLE X Thirty-five grams of9b-(p-chlorphenyl)-1,2,3,9btetrahydro-1H-imidazo[2,l-a]isoindol-5-oneand 150 m1. of 60 percent hydrochloric acid are stirred and heated to aclear solution. Stirring is continued for 20 minutes after solid beginsto precipitate. The mixture is cooled and the solid is separated byfiltration. On recrystallization from ethanol there is obtained 2-(2-aminoethyl)-3-(p-chloropheny1) 3- hydroxyphthalimidine hydrochloride,m.p. 2435C.

Analysis: Calcd for C ,,H N OCl'HCl: C, 56.63; H, 4.76; N, 8.26; Cl,20.91. Found: C, 56.38; H, 4.57; N, 8.01; Cl, 20.9.

Seventeen grams of the phthalimidine hydrochloride from above, 20 g. ofp-toluenesulfonyl chloride and 200 ml. of pyridine are refluxed for 2hours and then the mixture is evaporated to dryness. Onrecrystallization of the residue from ethanol there is obtained 9b-(p-ch1oropheny1)-1,2,3,9b-tetrahydro-1-(p-tolysu1-fonyl)-1H-imidazo[2,1-a] isoindol-S-one, m.p.

Analysis: Calcd for C H ClN O S: C, 62.93; H, 4.34; N 6.38; Cl, 8.08; S,7.30. Found: C, 63.24; H, 4.61; N, 6.15; Cl, 7.91; S, 7.3.

Ten grams of 9b-(p-chloropheny1 )-1 ,2,3,9btetrahydro-1-(p-tolylsulfonyl)1H-imidazo[2,1- a]isoindol-5-one aredissolved in 25 ml. of percent sulfuric acid and stirred at roomtemperature for /2 hour. The solution is quenched with ice water, thenfi1 tered to separate some precipitated solid. The filtrate whichcontains the sulfate salt of 4-ch1oro-2-(2- imidazolin-Z-yl)benzophenoneis cooled and made basic with a saturated sodium bicarbonate solution.The precipitated solid is separated by filtration and washed thoroughlywith water. On recrystallization from ethanol there is obtained5-(4-chlorophenyl)-2,3 dihydro-S H-imidazo [2,1-a1isoindol-5-ol, m .p. 2l 5-7C., dec., as a white crystalline solid which is insoluble in waterand soluble in ethanol.

Analysis: Ultra Violet Absorption ETOH) tax. 223 ,u (e=19,000), infl.242.5 ,u. (=8,300), n ..x,) 268.5 ,u (6=4,400), max. 272 ,u ($4,400);Ultra lolet Absorption (pH infl. 223 u (e==l8,000), max, 251 u (Fl1,000), max. 253 (c=l0,800); Infra Red Absorption (KBr) 1647 cm,2300-3200 cm.

Calcd for C ,H,;,N OC1: C, 67.49; H, 4.60; N, 9.40; C1, 1245. Found: C,67.18; H, 4.32; N, 9.68; C], 12.7.

ln a similar manner, the sulfate salts of 2-(2 imidaZo1in-2yl )-3'.,4'-diiodobenzophenone; 2 2- imidazolin-Z-yl )-2-methyl4 ',5'-dipropoxypropiophenone and 3 ,4diethoxy-2-( 2-imidaz0lin-2-yl)benzophenone are produced which are then respectively afford thefollowing compounds: 2,3-dihydro-5-(3,4-diiodopheny1)-5H-imidazo[2,1-alisoindol-5-ol;2,3-dihydro-5-isopropyl-7,8-dipropoxy-5H- imidazo[ 2, la]isoindol5-ol;and diethoxyphcnyl)-2,3-dihydro-5H-imidazo[ 2,1- alisoindol-Sol.

EXAMPLE XI Seventy grams of 9b-(p-to1y1)-1,2,3,9b-tetrahydro-1H-imidazo[2,1-a]isoindol5'one and 300 ml. of 48 percent hydrobromicacid are stirred and heated to a clear solution. Stirring is continuedfor fifteen minutes after precipitation. Thereafter, the reactionmixture is cooled and the precipitated solid, 2-(2-aminoethyl)-3-(p-tolyl)-3-hydroxyphthalimidine hydrobromide, is separated bydecantation, admixed with 40 g. of ptoluenesulfonyl chloride and 400 ml.of pyridine, heated to 100C. for 4 hours and evaporated to dryness.

Twenty grams of the residue 9b-(p-tolyl)-l,2,3,9btetrahydrol-(p-tolylsulfonyl l H-imidazo[ 2, l a]isoindol-S-one aredissolved in 50 ml. of 80 percent sulfuric acid and stirred at roomtemperature for one hour. The reaction mixture which contains thesulfate salt of 2-(2-imidazolin-2yl )-4'-methylbenzophenone is thencooled by the addition of ice water and made alkaline by the addition ofa lON sodium hydroxide solution. The precipitated solid is separated bydecantation and recrystallized from dioxan to obtain crystalline 2,3-dihydro-5-( 4-tolyl )-5H-imidazo[ 2, l -a]isoindol-5-ol, m.p. 208-210C.

In a similar manner, the following sulfates are synthesized:4-hexyl-2-(2-imidazolin-2-yl)benzophenone; 4- amino-2-(2-imidazolin-2-yl )benzaldehyde; 4'-chloro-2-(2-imidazolin-2-yl)-2-phenylacetophenone; and 2-(2-imidazolin-2-yl)phenyI-Z-thienyl ketone which are then contacted witha base to respectively afford the following: 5-( 4-hexylphenyl)2,3-dihydro-5H- imidazo[2,l-a]isoindol-5-ol; 8-amino-2,3-dihydro-5H-imidazo 2, l -a isoindol-S -l; 8-chloro-5-( 4- ethylphenyl)-2,3-dihydro-H-imidazo[2 l -a]isoindol 5-ol; and2,3-dihydro-5-(2-thienyl)-5H-imidazo[2,la]isoindol-S-ol.

EXAMPLE XII Thrity-five grams of9b-phenyl-l,2,3,9b-tetrahydrolH-imiadzo[2,l-a]isoindol-5-one and 150 ml.of 50 percent hydrochloric acid are stirred and heated to a clearsolution. Stirring is continued for 30 minutes after solid begins toprecipitate. The mixture is cooled and the solid is separated byfiltration. On recrystallization from ethanol there is obtained2-(2-aminoethyl)-3- phenyl-3-hydroxyphthalimidine hydrochloride.

Seventeen grams of the phthalimidine hydrochloride from above, g. ofp-butoxyphenylsulfonyl chloride and 200 ml. of pyridine is refluxed fortwo hours and then the mixture is evaporated to dryness. Onrecrystallization of the residue from ethanol there is obtained9b-phenyl-l ,2,3,9b-tetrahydrol p-butoxyphenylsulfonyl)-lH-imidazo[2,l-a]isoindol-5-one which is admixed with ml. of 95 percent sulfuricacid for one hour. The reaction mixture which contains the sulfate saltof 2-(2-imidazolin-2-yl) benzophenone is then cooled by the addition ofice water and made alkaline by the addition of a 5N potassium hydroxidesolution. The product is then separated by filtration and recrystallizedfrom dioxan to afford 2,3-dihydro-5-phenyl-5H-imidazo[2,la]isoindol-5-ol, m.p. 207C., as a white crystalline solidwhich is insoluble in water and soluble in dimethylacetamide andethanol.

Analysis: Ultra Violet Absorption (95% ETOH) infl. 225 ,u. (Fl4,900),max. 268 p. (F4,200); Ultra Violet Absorption (pHl) max. 250 p.(Fl3,500); Infra Red Absorption (KBr) 1660 cm, 2300-3000 cm.

Calcd for C H N O: C. 76.77; H, 5.63: N. ll.20. Found: C, 76.63; H,5.66; N, 11.0.

Similarly, the sulfate salts of 2-(2-imidazolin-2-yl)-4-methylbenzophenone and 2-(2-imidazolin-2-yl)-6- propylbenzophenone areproduced which are then converted to 2,3-dihydro-8-methyl-5-phenyl-5H-imidazo[2,l-a]isoindol-5-ol and 2,3-dihydro-5-phenyl-6-propyl-5H-imidazo[ 2, l -a]isoindol-5-ol.

EXAMPLE XIII Forty grams of 9b-(p-bromophenyl)-l ,2,3,9btetrahydrolH-imidazol 2, l -a]isoindol-5-one and 200 ml. of 50 percent hydrochloricacid are stirred and heated to a clear solution. Stirring is continuedfor 20 minutes after solid begins to precipitate. The mixture is cooledand the solid is separated by filtration. On recrystallization fromethanol there is obtained 2-(2- aminoethyl )-3-( p-bromophenyl )-3-hydroxyphthalimidine hydrochloride.

Twenty grams of the phthalimidine hydrochloride from above, 24 g. ofp-bromophenylsulfonyl chloride and 250 ml. of pyridine are refluxed for3 hours and then the mixture is evaporeated to dryness. Onrecrystallization of the residue from methanol there is obtained 9b-(p-bromophenyl )1 1,2,3 ,9b-tetrahydol pbromophenylsulfonyl l H-imidazo[2, 1 -a]isoindol- 5-one which is hydrolyzed with sulfuric acid to affordthe sulfate salt of 4'-bromo-2-(2-imidazolin-2- yl)benzophenone which iscontacted with an aqueous sodiumhydroxide solution. The product is thenseparated by filtration to afford 5(4-bromophenyl)-2,3-dihydro-5H-imidazo[ 2, l -a]isoindol-5-ol, m.p. l94-6C., as a whitecrystalline solid which is soluble in dimethylacetamide and hot ethanol.

Analysis: Ultra Violet Absorption (95% ETOH) max. 228 p. (Fl5,300). max.268 u (F4,800), max. 274 p. (F4,800); Ultra Violet Absorption (pHl) max.250 p. (Fll,000). max, 270 p. (Fl0,500); Infra Red Absorption (KBr) I660cm", 2300-300 cm".

Calcd for C|GH|3N2OBTI C, 58.38; H, 3.98; N, 8.50; Br, 24,28. Found: C,58.25; H, 4.02; N, 8.46; Br 24.00.

In a similar manner, the following compounds are prepared:

3 ',4'-dichloro-2-( Z-imidazolin-Z-yl )benzophenone sulfate which isneutralized to afford 5-(3,4- dichlorophenyl)-2.3-dihydro-5H-imidazo[2,1a]isoindol-S-ol, m.p. 2035C., as a white crystalline solid which issoluble in hot dimethyl acetamide and hot ethanol.

Analysis: Ultra Violet Absorption (95 /o ETOH), infl. 228 u (F2l,200),max. 274 p. (F4,500), max. 281 u (F3500); Ultra Violet Absorption (pHl)max. 243 [.L (Fl2,200), max. 251 ;L(Fll,750),ll1fl.2,65 a (F9,000),infl. 278 u (F6,750); Infra-Red Absorption (KBr) l655 cm", 2300-3000 cm.

Calcd for C H CI N- O: C, 60.21; H, 3.79; N, 8.78;

C], 22.22. Found: C, 59.9l; H. 3.66; N, 8.66; CI, 22.30.

4-fluoro-2-(2-imidazolin-2-yl)benzophenone sulfate which is neutralizedto afford 5-(4-fluorophenyl)-2,3-dihydro-SH-imidazol2,]-a]isoindol-5-ol, m.p. 2l42 l6C., dec., as a whitecrystalline solid which is insoluble in water and soluble indimethylacetamide.

Analysis: Ultra Violet Absorption 95% ETOH), infl. 235 [.L (Fl2,000),infl. 242 l (910,200). max. 263 u (F6100), max. 2.68 p;( 5,600); UltraViolet Absorption (pHl)max. 25] (Fl3.000)', Infra Red Absorption (KBr)1640 cm", 2300-3000 cm.

Calcd for cmH N- OF: C, 7 l .62; H, 4.88; N, 10.44. Found: C, 7l.73; H,5.00; N, I068.

3 '-bromo-4 '-methy1-2-( 2-imidazolin-2- yl)benzophenone sulfate whichis neutralizedto afford 5-( 3-bromo-4-methylphenyl)-2,3-dihydro-5H-imidazol2,l-alisondol-S-Ol. m.p. 2335C., dec., as a white crystallinesolid which is insoluble in water and soluble 'in dimethylacetamide.

Analysis: Calcd for c,,H, -,BrN o; C, 59.47; H, 4.41; N, 8.16; Br,23.28. Found: C, 59.75; H, 4,60; N, 8.32; Br, 23.23.

EXAMPLE XIV Ninety grams of l,2,3,9b-tetrahydro-9b-phenyl-SH- imidazo[2, 1 -a]isoindol-5-one, 75 g. of ptoluenesulfonyl chloride and one literof pyridine are heated at reflux for 14 to 18 hours. The solution isevaporated in vacuo to dryness, the residue slurried with water and thenseparated by filtration. On recystallization from ethanol there isobtained 90 g. of 9bphcnyl-l ,2,3,9b-tetrahyrol -(p-tolylsulfonl )-5H-imidazol 2,1-a]isoindol-5-one, m.p. 158160C.

Ninety grams of the above prepared sulfonamide compound is dissolved in200 ml. of 80% sulfuric acid and is left at room temperature for 2hours. The solution is diluted with two volumes of water and extractedwith ether. The aqueous portion which contains the sulfate salt of2-(2-imidazolin-2-yl)benzopheonone is then neutralized with 50% sodiumhydroxide solution while keeping the temperature below C. The solid isseparated and washed with water. On recrystallization formdimethylformamide there is obtained 27 g. of 2,3-dihydro-5-phenyl-5H-imidazo [2,1 -a]isoindol-5-ol which has the sameanalytical characteristics as the product of Example Xll.

EXAMPLE XV Sixty grams of9b-(4-chlorophenyl)-1,2,3,9btetrahydro-5H-imidazo[2.1-a]isoindo1-5-one,60 g. of p-toluenesulfonyl chloride and 750 ml. of pyridine are heatedat reflux for fourteen hours. The reaction mixture is worked-up asdescribed in Example XIV to obwin 70 g. of9b-(p-chlorophenyl)-l,2,3,9B-tetrahydrol-(pto|ylsu1fonyl)-5H-imidazo[2,l-alisoindol-5-one, m.p. l69l7lC. which can be recrystallized fromethanol (m.p. 17()-2C.)

Forty-five grams of the above prepared sulfonamide compound is dissolvedin 100 ml. of 80 sulfuric acid and is left at room temperature for 2hours. The solution is diluted with two volumes of water and extractedwith ether. The aqueous portion which contains 4-chloro-2-(Z-imidazolin-Z-yl)benzophenone is neutralized with 50 71sodium hydroxide solution while keeping the temperature below 25C. Thesolid is separated, washed with water and recrystallized fromdimethylformamide to afford 23 g. of 5-(4-chlorophenyl)-2,3-dihydro-5H-imidazo[2.1-alisoindol-5-ol which has the same analyticalcharacteristics as the product of Example X.

The above procedure is repeated to react a l,2,3,9b'tetrahydro-lH-imidazo[2,1-a]isoindol-5-one of V1"- Xll with anappropriate sulfonyl halide, in pyridine. at a temperature within therange of about 80C. to above 1 15C. for a period of about 2 to about 10hours to afford the corresponding sulfonamide which is treated withabout 80 to about 100 percent sulfuric acid to yield an appropriateyl)benzophcnone sulfate which is neutralized to produce a2,3-dihydro-5H-imidazo[2,1-a]isoind0l-5-ol.

2-(2-imidazolin-2- EXAMPLE XVI Ten grams of2,3-dihydro-5-phenyl-5H-imidazo[2,1- alisoindol-5-ol, as described inExample Xll, are suspended in ml. of absolute ethanol and then saturatedwith a continuous flow of hydrochloric acid gas. The resulting solutionis filtered to remove impurities and on standing 2-(2-imidazo1in-2-yl)benzophenone hydrochloride precipitates as a whitecrystalline sold, m.p. l979C., dec.

Analysis: Ultra Violet Absorption ETOH) max. 250 a (e -12,800); InfraRed Absorption (KBr) 1647 cm, 2400-3200 cm.

Calcd for C H N O.HCl: C, 67.03; H, 5.27; N, 9.77; Cl, 12.36. Found: C,66.88; H, 5.33; N, 9.83; Cl, 12.50.

EXAMPLE XVI] Ten grams of 5-(4-chlorophenyl)-2,3-dihydro-5H-imidazo[2,l-a]isoindol-5-ol, as described in Example X, are suspended in75 m1. of absolute ethanol and then saturated with a continuous flow ofhydrochloric acid gas. The resulting solution is filtered, evaporated todryness and the residue recrystallized from ethanolethyl acetate toafford 4'-chloro-2-(2-imidazolin-2- yl)benzophenone hydrochloride, m.p.l702C., dec., as a white crystalline solid which is soluble in water.

Analysis: Ultra Violet Absorption (95 ETOH) infl. 223 mp. (6 19.100),max. 252 ma (6 12,100), max. 265 mp. (F12,300); Infra Red Absorption(KBr) 1647 cm, 23003200 cm Calcd for c,,-H, .,N oc1.Hc1; C, 59.80; H,4.40; N, 8.72; CI, 22.08.

Found: C, 59.63; H, 4.50; N, 8'.-72;

- Similarly, the following hydrochlorides are prepared:2-(2-imidaz0lin-2-yl)-3, 4-diiodobenzophenone hydrochloride;

2-( 2-imidazolin-2-yl )-2-methyl-4 propiophenone hydrochloride;

3', 4-diethoxy-2-(2-imidazolin-2-yl)benzophenone hydrochloride;

5 '-dipropoxy- 2-(2-imidaz0lin-2-yl)-4-methylbenzophen0ne hydrochloride;

4-hexyl-2-(2-imidazolin-2-yl)benzophenone hydrochloride;

4-amino-2-(2-imidazolin-2-yl)Benzaldehyde dihydrochloride;

EXAMPLE XVlll When the procedure of Examples X XV are re- EXAMPLE XX Twograms of l-(p-chlorophenyl)-l 23.4.5.6- hexahydro-2,5-benzoidiazocinedihydrochloride are dissolved in 50 ml. of water. A solution of l g. ofpotassium permanganate in 50 ml. of water is added dropwise over aperiod of /2 hour. The mixture is filtered to remove inorganic salts andthe filtrate is made basic with sodium carbonate solution. Theprecipitated solid is separated and washed with water. Onrecrystallization from ethanol there is obtained 5-(4-chlorophenyl)-2,3-dihydro-5H-imidazo alisoindol-S-ol which has the samephysical characteristics as the identical compound of Example X.

Similarly, 2,3-dihydro-5-(Z-phenethyl)- 5-H-imidazo [2,l-a]isoindol-5-olis obtained by the oxidation of lphenethyl-l,2,3,4,5,6-hexahydro-2,5-benzodiazocine 25 dihydrobromide with potassiumdichromate.

EXAMPLE XXl Repeating the procedure of Example XX to oxidize ahereinafter listed hexahydrobenzodiazocine, the followingdihydroimidazoisoindolol compounds are prepared:

HEXAHYDROBENZODlAZOClNE EXAMPLE XXII Four grams ofl,2,3,4,5,6-hexahydro-8,9-dimethyll phenyl-Z,S-benzodiazocine isdissolved in 100 ml. of acetone. A solution of 2 g. of potassiumchlorate in 100 ml. of water is added dropwise over a period of an hour.Thereafter, the mixture is filtered and evaporated to dryness to afford2,3-dihydro-7,8-dimethyl-5-H- imidazo[2,l-a]isoindol 5-01 which isrecrytsallized, from methanol.

Simiarly, l-ethyll ,2,3,4,5,6-hexahydro-2,5- benzodiazocine is oxidizedto afford 5-ethyl-2,3- dihydro-5H-imidazo[2,l-a]isoindol-5-ol.

EXAMPLE xxin One gram of l,2,3,4,5,6-hexahydrol-phenyl-2,5-benzodiazocine dihydrochloride is dissolved in ml. of water. A solutionof 0.5 g. of potassium permanganate in 25 ml. of water is added over aperiod of l hour. The mixture is filtered to remove precipitatedinorganic salts and the filtrate is made alkaline with a potassiumbicarbonate solution. The precipitated product is separated andrecrystallized from ethanol. The product obtained in this manner is2,3-dihydro-5-phenyl-5H- imidazo[2,l-a]isoindol-5-ol which has the samephysical characteristics as the identical compound of Example Xll.

In the same manner, l,2,3,4,5,6-hexahydro-l-(2,4-dimethoxyphenyl)-2,S-benzoidazocine is converted to2,3-dihydro-5-(2,4-dimethoxyphenyl)-5H- imidazo[2, l-a]isoindol 5-ol.

EXAMPLE XXIV When the oxidation procedures of the previous Examples arerepeated at temperature ranges from 20C. to C. for periods of up toabout 4 hours on the fol- DlHYDROlMlDAZOlSOlNDOLOLSl,2,3,4,5,6-hexahydro l-( pbromophenyl )-2,5'benzodiazocinedihydrochloride S-ol l,2,3,4,5,6-hexah dro-l-(pmethoxyphenyl)-..,5-benzo diazocine dihydrochloride l-benzyll,2,3.4,5,6-hexahydro-2,5-benzodiazocine dihydrobromide l .13,4.5,6-hexahydrol 2- thienyl )2,5-henzodiazocine dih drochloridehexahydro-2,5-benzodia1ocinc,

dihydrochloridc l,2,3,4,5,(i-hexzniydro-S- methyl- 1-phenyl-2,5-benzodiazocine dihydrochloride l,2,3,4,5,6-hexahydro-l(2pyridyl )-2 ,S-benzodiazocine dihydrochloride l,2,3,4,5,6-hexahydro-8.9 dimethoxyl p-tolyl )-2.5 benzodiazocinedihydrochloride 2.3-dihydro-5-( 4-methoxyphenyl )-5 H-imidazol 2,1-a]isoindol-S-ol 5-henzyl-2,3-dihydro-5 H- imidazo[ 2, l -a isoindol-S-olimidazol2,1-alisoindol-5-ol 2.3-dihydro-7-methyl-5-phenyl isoindol-S-olHEXAHYDROBENZODlAZOClNES 7.8- 2,5-benzodiazocinc 1.2

benzodiazocinc l,2.3.4.5.6-hcxahydro-X,9- dichlorol phenyl-Z,

benzod iazocine diazocinu benzodiamcine 2,5-bcnzodiazocine,3.4,5,6-hexahydrol 5.6-

tetrahyd ro-lnaphthyl 2,3-dihydro-S-(5,6,7,8- tetrahydro-Zmaphthyl )-5H- imidazol 2,1-2ilisoindol-5-ol 5-( 4-trifluoromethylphenyl 2,3-dihydro5H-imidazo [2.l-a1isoindol-5-ol 7,8-dichloro-2,3-dihydro- EXAMPLE xxvTen grams of l-(3,4-dichlorophenyl)-l,2,3,4,5,6-hexahydro-2,5-benzodiazocine dihydrochloride are dissolved in 250 ml. ofwater. A solution of 5.0 g. of potassium permanganate in 250 ml. ofwater is added over a period of two hours. The mixture is filtered toremove precipitated inorganic salts and the filtrate is made alkalinewith a sodium bicarbonate solution. The precipitate product is separatedand recrystallized from methanol. The product obtained in this manner is5-(3,4- dichlorophenyl )-2,3-dihydro-5H-imidazo[ 2, l alisoindol-S-olwhich has the same physical characteristics as the identical compound ofExample XIII.

Similarly, l-( 3,4-dibromophenyll ,2,3,4,5,6-hexahydro-9-methyl-2,S-benzodiazocinc dihydrobromide is oxidized toafford 5-(3,4-dibromophenyl)-2,3- dihydro-8-methyl-5H-imidazo[2, 1-a]isoindol-5-ol.

EXAMPLE XXVI When the oxidation procedure of Examples XX to XXV isrepeated employing the following hexahydrobenzodiazocines as startingmaterials, the hereinafter listed dihydroimidazoisoindolol compounds areproduced.

wherein R is selected from the group consisting of hydrogen. loweralkyl, phen (lower) alkyl, phenyl, monohalophenyl, dihalophenyl.mono(lower)alkylphenyl, di(lower) alkylphenyl. trifluoromethylphenyl,mono(lower)alkoxyphcnyl, di(lower)alkoxyphenyl, thienyl. pyridyl,furyland tetrahydro-2-naphthyl, and R is hydrogen. lower alkyl, andphen(lower)alkyl R is selected from the group consisting of hydrogen,halogen, amino, lower alkylamino, lower alkyl and lower alkoxy; R ishydrogen when R and R are dissimilar and when R and R are the same theyare both selected from the group consisting of hydrogen, halogen, loweralkyl and lower alkoxy; R is selected from the group consisting ofphenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphcnyl,di(lower)alkylphenyl, trifluoromethylphenyl, mono(lower)alkoxyphenyl;di(lower)alkoxyphenyl, thienyl,v pyridyl, furyl andtetrahydro-Z-naphthyl; n is 2; lower alkyl and lower alkoxy have fromone to six carbon atoms; and HX is a pharmacologically acceptable acidaddition salt.

2. A compound as described in claim I, formula (II) wherein R and R arehydrogen; and R is 4- chlorophenyl which is: 6-(4-chlorophenyl)-2,3,4,6-tetrahydropyrimido[ 2 l -a ]isoindol-6-ol.

HEXAHYDROBENZODIAZOCINES l-( p-ethoxyphenyl l ,2.3 ,4, 5-(4-ethoxyphenyl )-2,3 5,fi-hexahydro-2,5-bcnzodiazodihydro-SH-imidazol 2,l -a cine isoindol-5ol I 2,3,4,5 t'v-hexahydrol ,9-2,3-dihydro-5,8-dimethyldimethyl-2.5-benzodiazocine 8-ethyll .2 ,3,4,5.6-hexahydro l phenyl-2,5-bcnzodiazocine What is claimed is:

SH-imidazol 2, I -a lisoindol -5-ol 7-ethyl-2.3-dihydro-5-phenyl-5H-imidazo[ 2, l-a lisoindol -5-ol 2,3-dihydro-7,8-dimethyl-5-(2phenelhyl )-5H-imidazo [2,l-a1isoindol-5-ol tolyl)-5H-imidazo [2.l-alisoindol-S-ol 1. A compound selected from the group consisting of thosehaving the formulae:

(TIT) DIHYDROIMIDAZOISOINDOLOLS and i on chlorophenyl)-23,4,6-tctrahydropyrimido[2,la]isoindol-6-olhydrochloride.

4. A compound as described in claim 1, formula (II) wherein R. and R arehydrogen; and R is phenyl which is:2,3,4,o-tctrahydro-o-phenylpyrimido[2,la]isoindol 6-01.

5. A compound as described in claim 1, formula (II) wherein R and R; arehydrogen; and R is 3,4- dichlorophenyl which is: 6-(3,4-dichlorophenyl)-2,3.4,6-tetrahydropyrimido[ 2. l -a]isoindol-6-ol.

6. A compound as described in claim 1, formula (ll) wherein R and R arehydrogen; and R is 4- bromophenyl which is: 6-(4-brophenyl)-2,3,4,6-tetrahydropyrimido 2, l -a]isoindol-6-ol.

7. A compound as described in claim 1, formula ([1) wherein R and R arehydrogen; and R is 5,6,7,S-tetrahydro-Z-naphthyl which is: 6-(5,6,7,8-tetrahydro-2-naphthyl')-2,3,4,6- tetrahydropyrimid[2,ll-alisoindol-6-ol.

8. A compound as described in claim I, formula (II) wherein R r and Rare hydrogen which is: 2,3,4,6- tetrahydropyrimido[2. l-a]isoindol-6-ol.

9. A compound as described in claim 1, formula (ll) wherein R and R arehydrogen; and R is methyl which is:2,3,4,6-tetrahydro-6-methylpyrimido[2,la]isoindol 6-ol.

10. A compound as described in claim 1, formula (ll) wherein R and R arehydrogen; and R is benzyl which is: 6-benzyl-2,3,4,6-tetrahydropyrimido[ 2,1- a]isoind0l-6-ol.

11. A compound as described in claim 1, formula (II) wherein R and R arehydrogen; and R is butyl which is: 6-butyll2,3,4,6-tetrahydropyrimido[2,l -a]isoind0l- 6-01.

12. A compound as described in claim 1, formula (Il) wherein R and R arehydrogen; and R is 3-amino-4- chlorophenyl which is:6-(3-amino-4-chlorophenyl)- 2,3,4,6-tetrahydropyrimido[2, l-a]isoindol-6-ol.

13. A compound as described in claim 1, formula (II) wherein R and R arehydrogen; and R is 4-tolyl which is: 2,3,4.6-tetrahydro-6-(4-tolyl)pyrimido[ 2, l alisoindol--ol.

14. A compound as described in claim 1, formula (II) wherein R and R arehydrogen; and R is 2-thienyl which is: 2,3,4,6-tetrahydro-6-( 2- thienyl)pyrimido[2, l -a]isoindol-6-ol.

. UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. 3,898,226

. DATED I August 5,1975 p 1 f 3 INVENTOWS) I Theodore S. Sulkowski It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Q Column 2: structure U is incorrect. Should be:

R OH

Column 4: structure (2) is incorrect. Should be:

CH CH NH 3 OH .HX

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. 3,898,226 DATED 3 August 5, 1975 |NVENT0R(5) 1 Theodore S.Sulkowski It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Page 2 of 3 Column 4: structure (3) is incorrect. Should be:

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. 3,393,22 DATED I August 5,1975 Page 3 of 3 INVENT0R(5) ITheodore S.Su1kowski It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 9, line 5: imidazoline ring of structure is lacking an NH group.Should be:

Signed and Scaled this Sixth Day Of March I979 [SEAL] Army.-

RUTH C. MASON DONALD w. BANNER Arresting Ojficer Commissioner of Parentsand Trademarks

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULAE
 2. A compound as described in claim 1, formula (II) wherein R2and R3 are hydrogen; and R4 is 4-chlorophenyl which is:6-(4-chlorophenyl)-2,3,4,6-tetrahydropyrimido(2,1-a)isoindol-6-ol.
 3. Anacid addition salt as described in claim 1, formula (III) wherein R2 andR3 are hydrogen; R5 is 4-chloropheny; and HX is hydrochloride which is:6-(4-chlorophenyl)-2,3,4,6-tetrahydropyrimido(2,1-a)isoindol-6-olhydrochloride.
 4. A compound as described in claim 1, formula (II)wherein R2 and R3 are hydrogen; and R4 is phenyl which is:2,3,4,6-tetrahydro-6-phenylpyrimido(2,1-a)isoindol 6-ol.
 5. A compoundas described in claim 1, formula (II) wherein R2 and R3 are hydrogen;and R4 is 3,4-dichlorophenyl which is: 6-(3,4-dichlorophenyl)-2,3,4,6-tetrahydropyrimido(2,1-a)isoindol-6-ol.
 6. Acompound as described in claim 1, formula (II) wherein R2 and R3 arehydrogen; and R4 is 4-bromophenyl which is:6-(4-brophenyl)-2,3,4,6-tetrahydropyrimido(2,1-a)isoindol-6-ol.
 7. Acompound as described in claim 1, formula (II) wherein R2 and R3 arehydrogen; and R4 is 5,6,7,8-tetrahydro-2-naphthyl which is:6-(5,6,7,8-tetrahydro-2-naphthyl)-2,3,4,6-tetrahydropyrimido(2,11l-a)isoindol-6-ol.
 8. A compound as described in claim 1, formula (II)wherein R2, r3 and R4 are hydrogen which is:2,3,4,6-tetrahydropyrimido(2,1-a)isoindol-6-ol.
 9. A compound asdescribed in claim 1, formula (II) wherein R2 and R3 are hydrogen; andR4 is methyl which is:2,3,4,6-tetrahydro-6-methylpyrimido(2,1-a)isoindol 6-ol.
 10. A compoundas described in claim 1, formula (II) wherein R2 and R3 are hydrogen;and R4 is benzyl which is:6-benzyl-2,3,4,6-tetrahydropyrimido(2,1-a)isoindol-6-ol.
 11. A compoundas described in claim 1, formula (II) wherein R2 and R3 are hydrogen;and R4 is butyl which is:6-butyl12,3,4,6-tetrahydropyrimido(2,1-a)isoindol-6-ol.
 12. A compoundas described in claim 1, formula (II) wherein R2 and R3 are hydrogen;and R4 is 3-amino-4-chlorophenyl which is:6-(3-amino-4-chlorophenyl)-2,3,4,6-tetrahydropyrimido(2,1-a)isoindol-6-ol.13. A compound as described in claim 1, formula (II) wherein R2 and R3are hydrogen; and R4 is 4-tolyl which is:2,3,4,6-tetrahydro-6-(4-tolyl)pyrimido(2,1-a)isoindol-6-ol.
 14. Acompound as described in claim 1, formula (II) wherein R2 and R3 arehydrogen; and R4 is 2-thienyl which is:2,3,4,6-tetrahydro-6-(2-thienyl)pyrimido(2,1-a)isoindol-6-ol.